ABSTRACT As the sole conduit between mother and offspring, the placenta is essential fetal development in eutherian mammals. A unique process in placental development is the fusion of trophoblasts to form the multinucleated polarized syncytiotrophoblast (STB) layer that serves as the primary site for maternofetal exchange. While many aspects of placental development have been well studied, an integrative global analysis of syncytialization and understanding of the epigenetic processes orchestrating syncytial fusion is absent. Our preliminary studies leveraging multiple genome-wide approaches (RNA-seq, genome- scale DNA methylation and ChIP-seq) suggest that gain in activating histone acetylation is the predominant epigenomic shift in syncytializing BeWo cells. Based on these findings, we hypothesize that histone acetylation at H3K27ac/ H3K9ac mediated via CBP and p300 histone acetyltransferases (HATs) represents a fundamentally conserved epigenetic process required for syncytialization. The proposed exploratory studies will address two main questions relating to this postulate. Utilizing trophoblast-specific conditional knockouts, Specific Aim 1 will examine the role of CBP/ p300 signaling in the placenta. Experiments will evaluate placental, labyrinth and vasculature development, markers of syncytialization and syncytial fusion in CBPfl/fl:Cre+ (CBP-CKO) and p300fl/fl:Cre+ (p300-CKO) mice, relative to respective flox-control (fl/fl:Cre-) littermates. The studies will provide in vivo functional validation for findings from BeWo cells. Studies in Specific Aim 2 will deduce coordinated changes in gene expression, DNA methylation (5-mc and 5-hmc), histone modifications and three-dimensional genome organization in primary human villous cytotrophoblasts from term placenta tissue. By merging expression profiling and epigenetic analysis, these studies will deduce underlying chromatin associated processes in syncytialization and extend findings from BeWo cells to primary trophoblasts. Collectively, these studies will provide a mechanistic link between histone acetyltransferases CBP/p300 and placental development and generate an important new resource in understanding key transcriptional and epigenomic networks in the syncytialization process.